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Vol. 112. Núm. 8.
Páginas 725-734 (Septiembre 2021)
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Vol. 112. Núm. 8.
Páginas 725-734 (Septiembre 2021)
Open Access
Malignant Syphilis: A Systematic Review of the Case Reports Published in 2014-2018
Sífilis maligna: revisión sistemática de los casos publicados entre los años 2014-2018
O. Wibisonoa,b,
Autor para correspondencia
, I. Idrusa, K. Djawada,b
a Servicio de Dermatología y Venereología, Facultad de Medicina de la Universidad de Hasanuddin, Makassar, Indonesia
b Hospital Dr. Wahidin Sudirohusodo, Makassar, Indonesia
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Tablas (2)
Table 1. Características demográficas y los factores de riesgo de sífilis en pacientes con sífilis maligna.
Table 2. Studies on malignant syphilis published in 2014–2018.
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Malignant syphilis (MS) is a rare manifestation of secondary syphilis which mainly occurs in immunocompromised individuals such as those coinfected with human immunodeficiency virus (HIV). However, recent reports have described MS in immunocompetent individuals. To describe the characteristics of individuals with MS and associated risk factors, a review of case reports published from 2014 to 2018 was conducted. Out of 45 published case reports, 33 cases (73%) occurred in HIV-positive individuals with majority having CD4 counts <500 cells/mm3. Of the 12 cases (27%) in HIV-negative individuals, half had comorbidities such as diabetes mellitus, alcoholism, drug abuse, psoriasis, and hepatitis. The most frequent manifestation of MS was ulceronodular cutaneous lesions with central adherent crust, which affected the face, trunk, and limbs. Given the increasing number of MS regardless of the immune status, dermatologists and general practitioners should be vigilant to allow early diagnosis and treatment, hence reducing their morbidity.

Malignant syphilis
Treponema pallidum
Immune deficiency
HIV infection

La sífilis maligna (SM) es una manifestación poco común de la sífilis secundaria. Esta se presentará principalmente en individuos inmunodeprimidos, como es el caso de los pacientes con una coinfección por el virus de la inmunodeficiencia humana (VIH). Sin embargo, recientemente se han descrito casos de SM también en individuos inmunocompetentes. Se realizó una revisión de los casos publicados entre el año 2014 y el 2018 para recoger las características de los pacientes con SM, así como los factores de riesgo asociados. De los 45 casos publicados, 33 casos (73%) ocurrieron en personas VIH positivas, la mayoría con recuentos de CD4 < 500 células/mm3. De los 12 casos (27%) en pacientes VIH-negativo, la mitad tenía comorbilidades como diabetes mellitus, alcoholismo, abuso de drogas, psoriasis y hepatitis. La manifestación más frecuente de la SM fueron las lesiones cutáneas ulcero – nodulares, las que presentaban una costra central adherente, y que afectaban la cara, el tronco y las extremidades. Dado el creciente número de SM, independientemente del estado inmunológico, los dermatólogos y médicos generales deben tener en cuenta la existencia de esta entidad para así poder realizar un diagnóstico y tratamiento oportuno, reduciendo de esta manera la morbilidad asociada.

Palabras clave:
Sífilis maligna
Treponema pallidum
Inmuno deficiencia
Infección por VIH
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Syphilis is an infection caused by Treponema pallidum, a spirochete bacterium that exclusively infects humans.1 Malignant syphilis (MS), also known as syphilis maligna, lues maligna, or rupioid syphilis, is a rare aggressive form of secondary syphilis.1 The term “rupioid” stems from the rupia or “oyster-like” appearance of these lesions, describing well-demarcated plaques with thick, lamellate, and adherent crusts on the surface that resemble an oyster shell.2 In 1859, the French dermatologist Pierre Bazin first used the term malignant to describe a case of secondary syphilis, and in 1896, at the Third International Congress of Dermatology in London, the Danish dermatologist Haslund and German dermatologist Neisser, independently classified MS as a rare, aggressive, ulcerating form of secondary syphilis and not an early form of tertiary syphilis, as had previously been assumed.1,3 It is distinguished from classical secondary syphilis based on a more severe general clinical picture and the presence of pleomorphic and ulceronecrotic skin lesions.4

MS presents as crusted or scaly papules and plaques that can ulcerate or become necrotic.5 The exanthem mainly affects the trunk and limbs, although the face, scalp, mucous membranes, palms, and soles can also be affected. Palpable peripheral lymphadenopathy, fever, and constitutional symptoms are commonly observed in patients with the disease. There have been only a limited number of reports of MS published in medical literature, and most of the reported cases have been in immunocompromised individuals, particularly those infected with human immunodeficiency virus (HIV).6 Syphilis and HIV co-infection can lead to an increased HIV viral load, concomitantly with a decreased CD4+ cell counts, greatly increasing the risk of MS, especially if untreated.7,8 Before the HIV pandemic, MS was extremely rare; between 1900 and 1988, only 14 cases had been published in English language. At present, it is estimated that up to 7% of all syphilis cases in immunocompromised patients meet the criteria for MS, often presenting as the first clinical manifestation of HIV infection.4 However, some reports on MS in immunocompetent individuals have been recently published.9,10 We conducted a systematic review of case reports on MS published between 2014 and 2018 to analyze demographic and risk factors of MS.


In order to review clinical, laboratory, and therapeutic data from patients with documented MS, we searched 2 databases (PubMed and Google Scholar) for literature published between 2014 and 2018, using the following terms: malignant syphilis OR lues maligna OR rupioid syphilis OR ulceronodular syphilis (Fig. 1). Our literature search yielded 39 articles, which were independently reviewed by 2 investigators, and any disagreement was resolved by consensus. We included all studies where the diagnosis was documented by serology or any combination of serology, pathologic findings, and immunostaining. Studies without positive serologic tests were not included. The inclusion criteria for the articles were: (1) case report with one of the aforementioned expressions in the title; (2) article in English; (3) articles published between 2014 and 2018; and (4) contain all the necessary information (gender, age, sexual behavior (heterosexual, bisexual or homosexual), location and description of the lesions, onset, serology and histopathology results, HIV status, immunostaining, treatment and post-treatment reactions, outcome). In total, 36 of the 39 articles were considered relevant and met the inclusion criteria. From those selected articles, we collected a total of 45 cases of MS.2,3,9–39 We extracted the details on each case and recorded it on a spreadsheet Microsoft Excel 2016. We used Microsoft Excel 2016 to produce basic descriptive statistics (frequencies, percentages, and medians) of the data. We did not do any hypothesis testing.

Figure 1.

Search flowchart.

ResultsDemographic characteristics

The majority (84%) of the patients were male, and the patients had a median age of 41 years (range: 20–86 years). The highest incidence was in the 40-44 years age group (Table 1). There was minimal information available regarding high-risk behaviors (possibly related to syphilis acquisition) in the cases we reviewed.

Table 1.

Características demográficas y los factores de riesgo de sífilis en pacientes con sífilis maligna.

Characteristics  Patients (n)  (%) 
○ Male  38  84.4 
○ Female  15.6 
Age group     
○ 20-24  6.7 
○ 25-29  15.6 
○ 30-34  2.2 
○ 35-39  20 
○ 40-44  13  28.9 
○ 45-54  17.8 
○ 55-64  4.4 
○ >65  4.4 
Positive serology     
Non-treponemal (VDRL, RPR)  41  – 
Treponemal (FTA-ABS, TPHA, TPPA)  35  – 
HIV status     
○ Positive  33  73.3 
○ Negative  12  26.7 
HIV (+) CD4 count (cells/mm3   
○ <200  24.2 
○ 200-499  17  51.5 
○ >500  15.2 
○ Not mentioned  9.1 
○ BPG  29  64.4 
○ Penicillin G  15.6 
○ Doxycycline  13.3 
○ Ceftriaxone  6.7 
○ Positive  20 
○ Negative  36  80 

BPG: Benzathine Penicillin G; JHR: Jarisch-Herxheimer Reaction; VDRL: Venereal Disease Research Laboratory; RPR: Rapid Plasma Reagin; FTA-ABS: Fluorescent Treponemal Antibody Absorption; TPHA: Treponema Pallidum Hemagglutination Assay.

No percentage can be given because there are no pertinent data for the remainder of the cases.

Clinical and laboratory characteristics

The clinical manifestations are reported on Table 2. The most frequent clinical manifestations were ulceronodular cutaneous lesions with adherent crust on the central surface affecting the face, trunk, and/or limbs (Table 2). Serological data were available for 44 out of 45 cases. The syphilis diagnosis was confirmed by nontreponemal and treponemal tests, which were reported as positive for 41 and 35 cases, respectively. Most (73%) patients were HIV-positive; among those, 51% had a CD4 cell count range of 200-499 cells/mm3. Notably, of the 12 immunocompetent patients, 6 (50%) had a comorbidity, such as diabetes mellitus, alcoholism, drug abuse, psoriasis, or hepatitis.

Table 2.

Studies on malignant syphilis published in 2014–2018.

No.  References  Race, Sex, Age (years), Sexual orientation  HIV status CD4 count (cells/mm3)/other  Location of the lesions  Onset (before admission)  Serological test results  Histopathology  Immunostaining/microorganism staining  Treatment  JHR  Resolution time/improvement 
1.  Dos Santos, et al., 2014 11  African, male, 27, MSM  HIV+  Forehead, back, lower limbs  3 months  VDRL 1:128  Perivascular mixed inflammatory infiltrate and granuloma in the dermis  NA  Doxycycline 100 mg/12 hours/PO for 3 weeks  −  3 weeks 
      340              Prophylactic hydrocortisone 200 mg IV   
2.  Cid, et al., 2014 12  Male, 42  HIV+  Face, scalp, trunk, limbs  8 days  RPR 1:64  Abundant histiocytes, giant cells and plasma cells in the dermis  Benzathine penicillin G 2.4 mU/week/IM for 3 weeks  −  3 weeks 
      442      IgG +           
            TPPA +           
3.  Cid, et al., 2014 12  Male, 33  HIV+  Scalp, cheek, upper limbs, trunk  5 months  RPR 1:16  Dense lymphocytes and plasma cells in the dermis  Benzathine penicillin G 2.4 mU/ week/ IM for 3 weeks  −  10 days 
      1294      TPPA +           
4.  Cid, et al., 2014 12  Male, 25  HIV+  Trunk, scalp  1 month  RPR 1:64  Dense lichenoid infiltrate, lymphocytes, histiocytes, and numerous plasma cells on the epidermis  Benzathine Penicillin G 2.4 mU/ week/ IM for 3 weeks  −  2 weeks 
      210      TPPA +           
5.  Bustos, et al., 2014 13  Male, 46  HIV−  Trunk, limbs, genitals, scalp  2 months  VDRL 1:32, FTA-ABS +  Heavy lymphocytes and histiocytes, abundant plasma cells in the dermis  NA  Benzathine penicillin G 2.4 mU/ week/ IM for 3 weeks  −  3 weeks 
      Hep B                 
6.  Requena, et al., 2014 4  Female, 29  HIV−  Face, trunk, limbs  2 weeks  VDRL 1:256  Dense lymphohistiocytic infiltrate rich in plasma cells, extended into the deep dermis  Benzathine penicillin G 2.4 mU/ week /IM for 3 weeks  3 months 
      Psoriasis      Treponemal test +           
7.  Kong, et al., 2014 14  Male, 36, MSM  HIV+  Face, trunk  3 weeks  VDRL 1:128  Granulomatous, lymphocytes, and plasma cells in the dermis  NA  Benzathine penicillin G  −  Improved 
8.  Navarrete, et al., 2015 8  White, male, 25  HIV+  Face, trunk, limbs, penis  3 months  RPR 1:512  Dense infiltrate of plasma cells, lymphocytes, and histiocytes  Benzathine penicillin G 2.4 mU/ week /IM for 3 weeks  −  1 week 
      236      MHA-TP +           
9.  Devkota, et al., 2015 15  African American, male, 20, MSM  HIV+  Trunk, face, and upper limbs  1 month  RPR 1:128,  Lichenoid lymphohistiocytic infiltrate with plasma cells  Doxycycline 100 mg/ 12 hours/ PO for 3 weeks  3 weeks 
      276      FTA-ABS +           
10.  Jalili, et al., 2015 16  White, female, 47  HIV+  Upper limbs, lower limbs, trunk, head  1 month  IgM +  Perivascular and perifollicular infiltration of lymphocytes, many histiocytes and numerous plasma cells in the dermis  −  Benzathine penicillin G 2.4 mU/ week/ IM for 3 weeks  −  4 weeks 
      155      TPPA +        Prophylactic methylprednisolone 40 mg PO 1 hour before penicillin injections   
            TPHA 1:1280           
            VDRL 1:32           
11.  Jiu-Hong Li, et al., 2015 17  Asian, male, 38, heterosexual  HIV−  Face, trunk, limbs  1 month  TPPA +  Mixed perivascular infiltrate with neutrophils, lymphocytes, plasma cells, and histiocytes in the dermis  NA  Benzathine penicillin G 2.4 mU/ week/ IM for 3 weeks  −  Improved 
            RPR 1:128           
12.  Jiu-Hong Li, et al., 2015 18  Asian, male, 35  HIV−  Face, trunk, limbs  1 month  TPHA +  Perivascular infiltration of dense neutrophils, lymphocytes, plasma cells and histiocytes  NA  Benzathine penicillin G 2.4 mU/ week/ IM for 3 weeks  −  4 weeks 
      DM      RPR 1:256        Prophylactic prednisone 40 mg 1 day before starting penicillin   
13.  Wei-Ting Chang, et al., 2015 19  Asian, male, 22  HIV+  Face, trunk, limbs  1 week  RPR 1:4  Perivascular and interstitial infiltrate of neutrophils, lymphocytes, histiocytes, and some plasma cells in the dermis  NA  Penicillin G aqueous 24 mU/day/ IV for 2 weeks  −  Several days 
      360      TPHA 1:320           
14.  Wei-Ting Chang, et al., 2015 19  Asian, male, 26, MSM  HIV+  Face, trunk, limbs, genitalia  3 weeks  RPR 1:512  Dense lymphohistiocytic infiltrate in upper and middle dermis, numerous plasma cells  Penicillin G aqueous 12 mU/day/ IV for 18 days and ciprofloxacin for 7 days  −  21 days 
      88      TPHA 1:20.480           
15.  Hanson, et al., 2015 20  Male, 45  HIV+  Back, groin  5 weeks  RPR 1:256  Perivascular granulomatous dermatitis with rare plasma cells  Benzathine penicillin G 2.4 mU/ week/IM for 3 weeks  −  NA 
16.  Alves, et al., 2015 21  Male, 57, MSM  HIV−  Head, neck, trunk, limbs  4 months  RPR 1:128  Diffuse dermal inflammatory infiltrate composed of plasma cells, histiocytes, and lymphocytes, forming granulomas in the deeper dermis  NA  Benzathine penicillin G 2.4 mU/ week/IM for 3 weeks  −  Improved, healed completely in 6 weeks 
            TPHA 1:5120           
17.  Braue, et al., 2015 3  African-American, male, 36  HIV+  Head, face, neck, limbs  1 month  FTA-ABS +  Prominent dermal infiltrate of epithelioid histiocytes, poorly formed granulomas with giant cells, dermal perifollicular lymphohistiocytic infiltrate  −  Penicillin G aqueous 24 mU/day/ IV for 2 weeks with decreasing dose (because of JHR). then, benzathine penicillin G 2.4 mU/ week/IM for 3 weeks  1 week 
      450      RPR 1:1024           
18.  Yamashita, et al., 2015 22  Asian, male, 40, heterosexual  HIV+  Trunk, limbs  4 weeks  RPR + (5.4 RU, card method x4)  Dermal vessels showed venulitis with extravasation of red blood cells, abundant neutrophils, histiocytes, a small number of plasma cells, and eosinophils  Penicillin G  −  NA 
      110      TP Ag + (2713.6 U)           
19.  Martinez, et al., 2016 23  Male, 54, bisexual  HIV+  Face, trunk, limbs, scrotum, palms, and soles  2 weeks  RPR 1:8  Not mentioned  Benzathine penicillin G 2.4 mU/ week/ IM for 3 weeks  NA 
      497      TPHA 1:2560           
20.  Muylaert, et al., 2016 24  Female, 50  HIV−  Face, trunk, limbs  4 months  VDRL 1:512  Confirmed secondary syphilis  NA  Benzathine penicillin G 2.4 mU then Ceftriaxone for 14 days  2 weeks 
      alcoholic      FTA-ABS +           
      drug user      IgG +           
            IgM +           
21.  Ortigosa, et al., 2016 25  White, female, 53  HIV−  Head, chest, limbs  20 days  VDRL 1:8  A cluster of non-caseating granulomas, plasma cells, rare eosinophils, endothelial swelling in the dermis  NA  Benzathine penicillin G 2.4 mU/ week/IM for 3 weeks and prednisone 60 mg PO daily  −  NA 
      DM      FTA-ABS +           
22.  Borges-costa, 2016 26  White, male, 42, heterosexual  HIV+  Trunk, upper limbs  2 weeks  TPHA and VDRL >1:256  NA  NA  Benzathine penicillin G 2.4 mU/IM  −  Improved 
23.  Borges-costa, 2016 26  White, male, 42, heterosexual  HIV+  Trunk, upper limbs  2-8 weeks  TPHA and VDRL >1:256  NA  NA  Benzathine penicillin G 2.4 mU/IM  −  Improved 
24.  Borges-costa, 2016 26  White, male, 42, heterosexual  HIV+  Head, trunk, upper limbs  2 months  TPHA and VDRL >1:256  NA  NA  Benzathine penicillin G 2.4 mU/IM  −  Improved 
25.  Sammet and Draenert, 2016 27  Male, 40, bisexual  HIV+  Trunk, generalized  3 previous episodes  TPPA  NA  NA  Ceftriaxone 2 g/day/ IV for 3 weeks  −  1 week 
      360      320.000 (2010)        Prophylactic prednisolone 1 mg/kg PO single dose   
            1.28 mill (2012)           
            320.000 (2014)           
26.  Krase, et al., 2016 28  Asian, male, 43  HIV−  Trunk, limbs  Several months  FTA-ABS +  Perivascular infiltrate of lymphocytes, numerous plasma cells, and scattered eosinophils  NA  Benzathine penicillin G 2.4 mU/ week /IM for 3 weeks  −  Healed completely in 3 months 
      CKD      RPR 1:4           
27.  Delgado and Caceres, 2017 29  Male, 25  HIV+  Face, chest, limbs  1 month  RPR 1:128, FTA-ABS +  Chronic, granulomatous, noncaseating infiltrate with plasma cells in the dermis  NA  Benzathine penicillin G  −  Improved 
28.  Mohan, et al., 2017 30  Male, 36  HIV+  Face, trunk, limbs  6 weeks  RPR 1:64  Lichenoid, psoriasiform, granulomatous dermatitis  Doxycycline 100 mg bd PO  −  1 week 
29.  Rao, et al., 2017 31  Asian, male, 35, heterosexual  HIV−  Face, trunk, limbs  1 month  VDRL 1:32  A dense collection of neutrophils, lymphocytes, few plasma cells in the dermis, PMN cells in the vessels wall (endarteritis obliterans)  NA  Benzathine penicillin G 2.4 mU/ week IM  −  Improved 
            TPHA 1:60           
30.  Johnson and Spivak, 2017 32  Male, 41  HIV+  Right foot, left chest  9 months  RPR 1:1024  Abundance of plasma cells and endothelial hyperplasia  −  Benzathine penicillin G 2.4 mU/ week/IM for 3 weeks  −  72 hours 
31.  Mena Lora, et al., 2017 33  Male, 58, MSM  HIV+  Trunk, limbs, testicles  2 weeks  RPR 1:256  Dense dermal plasma cell infiltrates with an overlying purulent serum crust and reactive hyperplastic epidermal changes  −  Benzathine penicillin G 2.4 mU/ week/IM single dose  −  1 week 
32.  Faraone and Fortini, 2017 34  White, female, 86, Heterosexual  HIV−  Tongue, face, trunk, limbs  4 months  TPHA 1:10.240  Epithelial ulceration and an intense perivascular inflammatory infiltrate of the lamina propria, rich in plasma cells  NA  Ceftriaxone for 2 weeks  −  Rapid (healed completely in 1 month) 
            VDRL +           
33.  Gevorgyan, et al., 2017 35  Male, 41  HIV+  Face, trunk, limbs, scalp, soles  4 months  TP Ab +  NA  NA  Benzathine penicillin G 2.4 mU/ week /IM for 3 weeks  2 days (healed completely in 1 month) 
      101      RPR 1:64           
      Drug user                 
34.  Zanella, et al., 2017 2  Male, 42  HIV+  Face, trunk, limbs, palmoplantar, oral and genital mucosa  2 months  VDRL 1:128  Lymphohistiocytic infiltrate with eosinophils and leucocytes, and epithelioid cells with multinucleated giant cells  NA  Benzathine penicillin G 2.4 mU/ week/IM for 3 weeks  Improved after treatment 
      140      TPHA +           
35.  Zanella, et al., 2017 2  Female, 42  HIV+  Face, tongue, back  2 months  VDRL 1:64  Deep perivascular dermatitis  NA  Ceftriaxone 2 g/day for 2 weeks  −  Improved after treatment 
      586      TPHA +        Prophylactic corticosteroids   
36.  Yap, et al., 2018 36  Male, 71  HIV+  Trunk, limb, palms, and soles  2 weeks  RPR 1:256  Epidermal ulceration with a dense dermal infiltrate consisting predominantly of mononuclear cells, abundant histiocytes, and plasma cells  NA  Aqueous penicillin G 12 mU/day/ IV for 15 days  −  2 weeks 
      252      TPPA +        Prophylactic prednisolone 60 mg/day for 5 days   
37.  Sun, et al., 2018 37  Asian, male, 23  HIV+  Face, trunk, limbs  2 months  Treponemal test +  NA  Doxycycline 100 mg/12 hours/ PO for 2 weeks  −  2 weeks 
      Decreased CD4                 
38.  Yang, et al., 2018 38  Asian, male, 52  HIV+  Face  6 months  Treponemal test +  NA  Benzathine penicillin G 2.4 mU/ week/IM for 3 weeks  −  1 week 
39.  Fustà-Novell X, et al. 2018 39  Hispanic, male, 39, MSM  HIV+  Palmoplantar, face, trunk, scalp  2 weeks  VDRL 1:128  Dermatitis lichenoid (lymphocytes, histiocytes, plasma cells).  Benzathine penicillin G 2.4 mU/ week/IM for 3 weeks  Improved 
40.  Fustà-Novell X, et al., 2018 39  Hispanic, male, 36, MSM  HIV+  Palmoplantar, nail, scalp, face  3 weeks  VDRL 1:250  Dermatitis spongiosa (histiocytes, plasma cells).  Penicillin G aqueous 24 mU/day/ IV for 15 days  Improved 
41.  Fustà-Novell X, et al., 2018 39  Hispanic, male, 54, MSM  HIV+  Palmoplantar, limbs  1 month  VDRL 1:512  Dermatitis lichenoid (lymphocytes, histiocytes, plasma cells).  −  Benzathine penicillin G 2.4 mU/ week/IM for 3 weeks  −  Improved 
42.  Fustà-Novell X, et al., 2018 39  Hispanic, male, 26, MSM  HIV+  Palmoplantar, scalp, limbs  1 month  VDRL 1:256  Dermatitis abscessed (lymphocytes, histiocytes, plasma cells).  −  Benzathine penicillin G 2.4 mU/ IM single dose  −  Improved 
43.  Mitteldorf, et al., 2018 7  Caucasian, male, 42  HIV+  Trunk  6 weeks  NA  Lichenoid infiltrate, histiocytes. and plasma cells in the dermis  Penicillin G aqueous 30 mU/ day/ IV for 2 weeks  −  Few weeks 
      312              Prophylactic prednisone 60 mg single dose   
44.  Pradhan, et al., 2018 9  Female, 35, heterosexual  HIV−  Face, trunk, limbs, genital, palm, sole, scalp  3 weeks  VDRL 1:64  Plasma cells in the vessel wall and thrombosed vessels in the dermis with endarteritis  NA  Doxycycline 100 mg/12 hours/ PO for 3 weeks  −  2 weeks 
            TPHA 1:160           
45.  Rockwood, and Nwokolo, 2018 10  White, male, 41, heterosexual  HIV−  Face, trunk, limbs, left testicular mass  2 weeks  TPPA +  Chronic epididymo-orchitis with occasional poorly formed granulomas  Doxycycline 100 mg/12 hours/ PO for 4 weeks  −  4 weeks 
            RPR 1:256           

Abbreviations: FTA-ABS, fluorescent treponemal antibody absorbed; IgG, immunoglobulin G; IgM, immunoglobulin M; JHR, Jarisch-Herxheimer reaction; IM; intramuscular; MSM, men who have sex with men; NA, not available; PO, per os (by mouth); RPR, rapid plasma regain; TP Ab, Treponema pallidum antibody; TPHA, Treponema pallidum hemagglutination test; TPPA, Treponema pallidum particle agglutination; VDRL, Venereal Diseases Research Laboratory.

Histological findings and immunostaining and microorganism staining

Skin lesions were reported and verified by histology in 37 of the 45 reviewed cases (Table 2). The most commonly reported histopathology features are lymphohistiocytic dermal infiltrate composed of plasma cells. Data on immunostaining and microorganism staining were given for 23 cases; T. pallidum was detected in 17 of those patients. In the remaining 6 patients, no spirochetes were detected (Table 2).

Treatment and outcome

Approximately two-thirds (64%) of the patients were treated with intramuscular benzathine penicillin G, and the remaining patients were treated with alternatives including as intravenous aqueous penicillin G, oral doxycycline, or intravenous ceftriaxone (Table 1). Nine patients (20%) experienced JHRs, of whom 7 were treated with prophylactic corticosteroids (Table 2).


We reviewed published case reports on 45 patients with MS, published in 2014-2018. It is well recognized that MS is commonly observed in immunosuppressed patients such as those with HIV infection. The pathogenesis of MS is unknown, but it is generally believed that immunosuppression due to HIV coinfection enables T. pallidum to become more virulent. Notably however, most of the HIV-positive patients had a CD cell count >200 cells/mm3, and thus, they were not deeply immunosuppressed.12 The loss of CD4 T cells that occurs as a result of HIV infection or other conditions4 leads to a greater action of cytotoxic T cells and neutrophils on the skin2 in MS. As a result, MS differs from conventional syphilis that occurs in individuals with intact immune systems. This reasoning is consistent with its occurrence in patients with comorbidities or debilitating disease as a cofactor. Our review revealed that 6 of the 12 HIV-negative patients (50%) had comorbidities such as diabetes mellitus, alcoholism, drug abuse, psoriasis, and hepatitis, which could have affected their immune function. The occurrence of MS in HIV-negative patients with comorbidities raises the possibility of aberrant immune response caused by these systemic conditions triggering a more severe skin manifestation and the possibility of a more virulent strains of Treponema, which already considered by other authors.4,32,38,39

MS is often seen in association with high nontreponemal titers and systemic symptoms.5 To guide the clinical diagnosis, in 1969, Fisher et al., proposed 4 criteria in order to identify this rare variant of syphilis, namely: (1) Comparable gross and microscopic morphology; a high titer serologic test for syphilis; a Jarisch-Herxheimer reactions (JHR); and a dramatic response to antibiotic therapy.40

Diagnosis by skin biopsy in affected patients is challenging because spirochetes are generally sparse in the skin lesions. Skin biopsy is, however, a recommended procedure to exclude other bacterial, fungal, and mycobacterial infections. Data obtained from special staining and dark-field microscopy may be insufficient to make a histologic diagnosis,33,40 but microscopic evaluation may reveal nonspecific inflammatory findings, such as histological patterns of dermal infiltrate with plasma cells and lymphocytes, sometimes granulomatous and vascular damage. Our review revealed that lymphohistiocytic dermal infiltrate with plasma cells was the most commonly reported histological feature.12 Immunohistochemistry is superior to silver stains for detecting spirochetes, but it is not always be available as a routine procedure.33

An increase in the incidence of JHR has been described both in patients with MS and in patients with HIV in general. Yang et al describe a rate of incidence of JHR as high as 34.6% in HIV-infected patients.41 In our review, JHR was reported in only 9 patients (20%), and of these 9 patients, 7 were provided with prophylactic corticosteroids. JHR is a transient immunological phenomenon seen commonly in patients during treatment of secondary syphilis; it manifests with constitutional symptoms such as fever, chills, headache, and myalgia, in addition to exacerbation of existing cutaneous lesions. The reaction usually occurs hours after the administration of an appropriate antibiotic and normally resolves without any intervention within 24 hours. JHR is more severe when the number of pathogens is abundant, consistent with a high-titer serological test being part of MS criteria. It should be managed symptomatically and does not require discontinuation of the appropriate antimicrobial treatment. Corticosteroids have been used to prevent the reaction, but there is no conclusive evidence regarding their benefit.35,42

Currently, there is no specific recommendations for MS treatment. The most commonly used treatment regimen is the same as that used for late latent syphilis (3 consecutive weekly intramuscular injections of benzathine penicillin, 2.4 million units/dose). In case of allergy to penicillin, treatment with ceftriaxone can be used. In resistant cases or relapses, prolonged therapy with high doses of penicillin is suggested.12,25 About 80% of the patients in our review were treated with penicillin, either intramuscularly or intravenously as aqueous solution, and all the patients had a rapid improvement in their condition following antibiotic treatment.


Our review included 45 case reports of MS published from 2014-2018, available on the PubMed and/or Google Scholar databases. Of the patients, 74% were HIV positive. Of the HIV-negative patients, half had a comorbidity such as diabetes mellitus, alcoholism, drug abuse, psoriasis, hepatitis. The majority of cases occurred in men (84%), the median age of presentation is 41 years with the 40-44 years old age group being the most frequently affected. The most frequent cutaneous manifestations were ulceronodular lesions with an adherent crust on the central surface affecting the face, trunk, and limbs. with half of patients with HIV infection having a CD4 cell count in the 200-499 cells/mm3 range. The majority of patients were treated with benzathine penicillin G or aqueous penicillin G, and all patients experienced a rapid clinical improvement following antibiotic therapy. JHR was reported in 20% of patients, despite the majority of them having been given prophylactic corticosteroids. In the face of the increased number of cases of this rare form of syphilis regardless of the immune status, dermatologists and general practitioners should be attentive to the occurrence of MS in order to allow early diagnosis and treatment, hence reducing their morbidity.

Conflicts of interest

The authors declare no conflicts of interest.


We would like to thank Hindawi Editage ( for English language editing.

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Please cite this article as: Wibisono O, Idrus I, Djawad K. Sífilis maligna: revisión sistemática de los casos publicados entre los años 2014-2018. Actas Dermosifiliogr. 2021.

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